Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Hypoxia-induced LAMB2-enriched extracellular vesicles promote peritoneal metastasis in gastric cancer via the ROCK1-CAV1-Rab11 axis

Oncogene volume 43, pages 2768–2780 (2024)Cite this article

Subjects

Abstract

Peritoneal metastasis is one of the most common risk factors contributing to the poor prognosis of gastric cancer. We previously reported that extracellular vesicles from gastric cancer cells could facilitate peritoneal metastasis. However, their impact on gastric cancer-induced peritoneal metastasis under hypoxic conditions remains unclear. This study aims to elucidate how hypoxia-resistant gastric cancer cell-derived extracellular vesicles affect the peritoneal metastasis of normoxic gastric cancer cells. Proteomic analysis revealed elevated levels of Caveolin1 and Laminin β2 in hypoxia-resistant gastric cancer cells and their corresponding extracellular vesicles. Importantly, Caveolin1 was found to play a central role in mediating Laminin β2 sorting into extracellular vesicles derived from hypoxia-resistant gastric cancer cells, and subsequently, extracellular vesicle-associated Laminin β2 promoted peritoneal metastasis in normoxic gastric cancer cells by activating the AKT pathway. Further investigation confirmed that Caveolin1 activation by Rho-related Coiled-coil kinase 1-mediated phosphorylation of Y14 residue is a key factor facilitating Laminin β2 sorting into extracellular vesicles. Moreover, Y14 phosphorylated- Caveolin1 enhanced Laminin β2 sorting by activating Rab11. Finally, our study demonstrated that a combined assessment of plasma extracellular vesicle-associated Caveolin1 and extracellular vesicle-associated Laminin β2 could provide an accurate predictive tool for peritoneal metastasis occurrence in gastric cancer.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Hypoxia increases the release of EVs and promotes gastric cancer cell metastasis.
Fig. 2: HRGC-EVs CAV1 promotes GC peritoneal metastasis in vivo and in vitro.
Fig. 3: CAV1 enriches EVs LAMB2 and promotes GC peritoneal metastasis via the AKT pathway.
Fig. 4: ROCK1 activated-CAV1 Y14 phosphorylation contributes to LAMB2 enrichment to EVs.
Fig. 5: Y14 phosphorylated CAV1 promotes EVs LAMB2 enrichment by activating Rab11.
Fig. 6: EVs CAV1 and EVs LAMB2 as biomarkers for predicting peritoneal metastasis of gastric cancer.

Similar content being viewed by others

Data availability

The data that supports the findings of this study are available in the article and Supplementary material of this article. Additional data are available from the corresponding author upon reasonable request.

References

  1. Rijken A, Lurvink RJ, Luyer MDP, Nieuwenhuijzen GAP, van Erning FN, van Sandick JW, et al. The Burden of Peritoneal Metastases from Gastric Cancer: A Systematic Review on the Incidence, Risk Factors and Survival. J Clin Med. 2021;10:4882.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71:209–49.

    Article  PubMed  Google Scholar 

  3. Mikuła-Pietrasik J, Uruski P, Tykarski A, Książek K. The peritoneal “soil” for a cancerous “seed”: a comprehensive review of the pathogenesis of intraperitoneal cancer metastases. Cell Mol Life Sci. 2018;75:509–25.

    Article  PubMed  Google Scholar 

  4. Jing X, Yang F, Shao C, Wei K, Xie M, Shen H, et al. Role of hypoxia in cancer therapy by regulating the tumor microenvironment. Mol Cancer. 2019;18:157.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Liao C, Liu X, Zhang C, Zhang Q. Tumor hypoxia: From basic knowledge to therapeutic implications. Semin Cancer Biol. 2023;88:172–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Kim JY, Lee JY. Targeting Tumor Adaption to Chronic Hypoxia: Implications for Drug Resistance, and How It Can Be Overcome. Int J Mol Sci. 2017;18:1854.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Yang Z, Shi X, Li C, Wang X, Hou K, Li Z, et al. Long non-coding RNA UCA1 upregulation promotes the migration of hypoxia-resistant gastric cancer cells through the miR-7-5p/EGFR axis. Exp Cell Res. 2018;368:194–201.

    Article  CAS  PubMed  Google Scholar 

  8. Jin Y, Che X, Qu X, Li X, Lu W, Wu J, et al. CircHIPK3 Promotes Metastasis of Gastric Cancer via miR-653-5p/miR-338-3p-NRP1 Axis Under a Long-Term Hypoxic Microenvironment. Front Oncol. 2020;10:1612.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Wang X, Che X, Yu Y, Cheng Y, Bai M, Yang Z, et al. Hypoxia-autophagy axis induces VEGFA by peritoneal mesothelial cells to promote gastric cancer peritoneal metastasis through an integrin α5-fibronectin pathway. J Exp Clin Cancer Res. 2020;39:221.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. van Niel G, D’Angelo G, Raposo G. Shedding light on the cell biology of extracellular vesicles. Nat Rev Mol Cell Biol. 2018;19:213–28.

    Article  PubMed  Google Scholar 

  11. Yoo S, Choi S, Kim I, Kim IS. Hypoxic regulation of extracellular vesicles: Implications for cancer therapy. J Control Release. 2023;363:201–20.

    Article  CAS  PubMed  Google Scholar 

  12. Ramteke A, Ting H, Agarwal C, Mateen S, Somasagara R, Hussain A, et al. Exosomes secreted under hypoxia enhance invasiveness and stemness of prostate cancer cells by targeting adherens junction molecules. Mol Carcinog. 2015;54:554–65.

    Article  CAS  PubMed  Google Scholar 

  13. Kamposioras K, Vassilakopoulou M, Anthoney A, Bariuoso J, Mauri D, Mansoor W, et al. Prognostic significance and therapeutic implications of Caveolin-1 in gastrointestinal tract malignancies. Pharmacol Ther. 2022;233:108028.

    Article  CAS  PubMed  Google Scholar 

  14. Wang Y, Song Y, Che X, Zhang L, Wang Q, Zhang X, et al. Caveolin‑1 enhances RANKL‑induced gastric cancer cell migration. Oncol Rep. 2018;40:1287–96.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Albacete-Albacete L, Navarro-Lérida I, López JA, Martín-Padura I, Astudillo AM, Ferrarini A, et al. ECM deposition is driven by caveolin-1-dependent regulation of exosomal biogenesis and cargo sorting. J Cell Biol. 2020;219:e202006178.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Lee H, Li C, Zhang Y, Zhang D, Otterbein LE, Jin Y. Caveolin-1 selectively regulates microRNA sorting into microvesicles after noxious stimuli. J Exp Med. 2019;216:2202–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Qin Y, Rodin S, Simonson OE, Hollande F. Laminins and cancer stem cells: Partners in crime? Semin Cancer Biol. 2017;45:3–12.

    Article  CAS  PubMed  Google Scholar 

  18. Kikkawa Y, Hashimoto T, Takizawa K, Urae S, Masuda H, Matsunuma M, et al. Laminin β2 variants associated with isolated nephropathy that impact matrix regulation. JCI Insight. 2021;6:e145908.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Shahbazi R, Baradaran B, Khordadmehr M, Safaei S, Baghbanzadeh A, Jigari F, et al. Targeting ROCK signaling in health, malignant and non-malignant diseases. Immunol Lett. 2020;219:15–26.

    Article  CAS  PubMed  Google Scholar 

  20. Simón L, Campos A, Leyton L, Quest AFG. Caveolin-1 function at the plasma membrane and in intracellular compartments in cancer. Cancer Metastasis Rev. 2020;39:435–53.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Hayer A, Stoeber M, Ritz D, Engel S, Meyer HH, Helenius A. Caveolin-1 is ubiquitinated and targeted to intralumenal vesicles in endolysosomes for degradation. J Cell Biol. 2010;191:615–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Meng F, Saxena S, Liu Y, Joshi B, Wong TH, Shankar J, et al. The phospho-caveolin-1 scaffolding domain dampens force fluctuations in focal adhesions and promotes cancer cell migration. Mol Biol Cell. 2017;28:2190–201.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Wong TH, Dickson FH, Timmins LR, Nabi IR. Tyrosine phosphorylation of tumor cell caveolin-1: impact on cancer progression. Cancer Metastasis Rev. 2020;39:455–69.

    Article  CAS  PubMed  Google Scholar 

  24. Barcelo J, Samain R, Sanz-Moreno V. Preclinical to clinical utility of ROCK inhibitors in cancer. Trends Cancer. 2023;9:250–63.

    Article  CAS  PubMed  Google Scholar 

  25. Shimokawa H, Sunamura S, Satoh K. RhoA/Rho-Kinase in the Cardiovascular System. Circ Res. 2016;118:352–66.

    Article  CAS  PubMed  Google Scholar 

  26. Kim JG, Mahmud S, Min JK, Lee YB, Kim H, Kang DC, et al. RhoA GTPase phosphorylated at tyrosine 42 by src kinase binds to β-catenin and contributes transcriptional regulation of vimentin upon Wnt3A. Redox biology. 2021;40:101842.

    Article  CAS  PubMed  Google Scholar 

  27. Thomas S, Overdevest JB, Nitz MD, Williams PD, Owens CR, Sanchez-Carbayo M, et al. Src and caveolin-1 reciprocally regulate metastasis via a common downstream signaling pathway in bladder cancer. Cancer research. 2011;71:832–41.

    Article  CAS  PubMed  Google Scholar 

  28. Glotfelty EJ, Tovar YRLB, Hsueh SC, Tweedie D, Li Y, Harvey BK, et al. The RhoA-ROCK1/ROCK2 Pathway Exacerbates Inflammatory Signaling in Immortalized and Primary Microglia. Cells. 2023;12:1367.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Veerman RE, Teeuwen L, Czarnewski P, Güclüler Akpinar G, Sandberg A, Cao X, et al. Molecular evaluation of five different isolation methods for extracellular vesicles reveals different clinical applicability and subcellular origin. J Extracell Vesicles. 2021;10:e12128.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Kalluri R, McAndrews KM. The role of extracellular vesicles in cancer. Cell. 2023;186:1610–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Dixson AC, Dawson TR, Di Vizio D, Weaver AM. Context-specific regulation of extracellular vesicle biogenesis and cargo selection. Nat Rev Mol Cell Biol. 2023;24:454–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Marie PP, Fan SJ, Mason J, Wells A, Mendes CC, Wainwright SM, et al. Accessory ESCRT-III proteins are conserved and selective regulators of Rab11a-exosome formation. J Extracell Vesicles. 2023;12:e12311.

    Article  PubMed  Google Scholar 

  33. Katzmann DJ, Odorizzi G, Emr SD. Receptor downregulation and multivesicular-body sorting. Nat Rev Mol Cell Biol. 2002;3:893–905.

    Article  CAS  PubMed  Google Scholar 

  34. Escudero CA, Lazo OM, Galleguillos C, Parraguez JI, Lopez-Verrilli MA, Cabeza C, et al. The p75 neurotrophin receptor evades the endolysosomal route in neuronal cells, favouring multivesicular bodies specialised for exosomal release. J Cell Sci. 2014;127:1966–79.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Aumailley M. The laminin family. Cell Adh Migr. 2013;7:48–55.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Shimada H, Noie T, Ohashi M, Oba K, Takahashi Y. Clinical significance of serum tumor markers for gastric cancer: a systematic review of literature by the Task Force of the Japanese Gastric Cancer Association. Gastric Cancer. 2014;17:26–33.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Natural Science Foundation of China (No. 32170791, 81972751, 82272853, 81972331, 81902998, 82203841,82102929). The funding source provided financial support for the study and did not have any other involvement in this study. The authors would like to acknowledge the Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education (China Medical University, Shenyang, China), and Clinical Cancer Research Center of Shenyang (China Medical University, Shenyang, China) for providing the space and equipment for conducting the experiments.

Author information

Authors and Affiliations

  1. Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, China

    Dongyang Li, Yue Jin, Xin He, Wenqing Lu, Zichang Yang, Xueying Zheng, Kezuo Hou, Shiying Tang, Bowen Bao, Jie Ren, Xiaojie Zhang, Jin Wang, Hongfei Yan, Xiujuan Qu, Yunpeng Liu & Xiaofang Che

  2. Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, China

    Dongyang Li, Yue Jin, Xin He, Wenqing Lu, Zichang Yang, Xueying Zheng, Kezuo Hou, Shiying Tang, Bowen Bao, Jie Ren, Xiaojie Zhang, Jin Wang, Hongfei Yan, Xiujuan Qu, Yunpeng Liu & Xiaofang Che

  3. Clinical Cancer Research Center of Shenyang, Shenyang, China

    Dongyang Li, Yue Jin, Xin He, Wenqing Lu, Zichang Yang, Xueying Zheng, Kezuo Hou, Shiying Tang, Bowen Bao, Jie Ren, Xiaojie Zhang, Jin Wang, Hongfei Yan, Xiujuan Qu, Yunpeng Liu & Xiaofang Che

  4. Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, Shenyang, China

    Dongyang Li, Yue Jin, Xin He, Wenqing Lu, Zichang Yang, Xueying Zheng, Kezuo Hou, Shiying Tang, Bowen Bao, Jie Ren, Xiaojie Zhang, Jin Wang, Hongfei Yan, Xiujuan Qu, Yunpeng Liu & Xiaofang Che

  5. Third Department of Medical Oncology, The Fifth People Hospital of Shenyang, Shenyang, China

    Jian Deng

Authors
  1. Dongyang Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yue Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xin He
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jian Deng
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Wenqing Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Zichang Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xueying Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Kezuo Hou
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Shiying Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Bowen Bao
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Jie Ren
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Xiaojie Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Jin Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Hongfei Yan
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Xiujuan Qu
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Yunpeng Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Xiaofang Che
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

XC, YL and DL conceived and designed this project. DL, YJ, XH, JD, WL, ZY, XZ, KH, XZ, JW and HY performed the experiments. ST, BB and JR analyzed the data. DL wrote the initial paper draft. XQ provided conceptual advice and helpful discussions. XC and YL modified the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Yunpeng Liu or Xiaofang Che.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, D., Jin, Y., He, X. et al. Hypoxia-induced LAMB2-enriched extracellular vesicles promote peritoneal metastasis in gastric cancer via the ROCK1-CAV1-Rab11 axis. Oncogene 43, 2768–2780 (2024). https://doi.org/10.1038/s41388-024-03124-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-024-03124-y

Search

Advanced search

Quick links